The proposed research is designed to test the feasibility and limits of a novel method developed for the selection of desired biological activities in vivo from random peptide libraries. The method will be adapted for the selection of peptide inhibitors of the HIV-1 protease. The utilities of selected inhibitors as models for the rational design of effective drugs and genes for use in AIDS therapy will be explored. In particular, HIV-1 protease inhibitor transgenes will be developed for a gene therapy approach to AIDS, targeting the function(s) of the protease in T4 cell killing. Recombinant HIV-1 protease will be inducibly expressed in streptomycin-resistant strains of E. coli along with a chimeric protein comprised of a natural substrate of the protease fused to a protein which confers streptomycin sensitivity on the cells when, and only when, the substrate is cleaved by the protease. For the random peptide libraries, an inducible "carrier" gene will be constructed encoding a chimeric protein comprised of the substrate domain described above fused to a reporter protein. Part or all of the substrate coding sequence will be replaced with random oligodeoxynucleotides. These libraries will be introduced into the strep-sensitive protease transformants and inhibitors of the HIV-1 protease will be identified by their ability to grow in the presence of streptomycin.